20-33680374-C-T

Position:

• chr20-33680374-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005225.3(E2F1):​c.304G>A​(p.Ala102Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00559 in 1,614,206 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0058 (27 hom.)
• Consequence: E2F1 NM_005225.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.78

Genes affected

E2F1 (HGNC:3113): (E2F transcription factor 1) The protein encoded by this gene is a member of the E2F family of transcription factors. The E2F family plays a crucial role in the control of cell cycle and action of tumor suppressor proteins and is also a target of the transforming proteins of small DNA tumor viruses. The E2F proteins contain several evolutionally conserved domains found in most members of the family. These domains include a DNA binding domain, a dimerization domain which determines interaction with the differentiation regulated transcription factor proteins (DP), a transactivation domain enriched in acidic amino acids, and a tumor suppressor protein association domain which is embedded within the transactivation domain. This protein and another 2 members, E2F2 and E2F3, have an additional cyclin binding domain. This protein binds preferentially to retinoblastoma protein pRB in a cell-cycle dependent manner. It can mediate both cell proliferation and p53-dependent/independent apoptosis. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0064412653).
• BP6: Variant 20-33680374-C-T is Benign according to our data. Variant chr20-33680374-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 785835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 609 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
E2F1	NM_005225.3	c.304G>A	p.Ala102Thr	missense_variant	2/7	ENST00000343380.6
E2F1	XM_047439961.1	c.304G>A	p.Ala102Thr	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
E2F1	ENST00000343380.6	c.304G>A	p.Ala102Thr	missense_variant	2/7	1	NM_005225.3	P1

Frequencies

GnomAD3 genomes AF: 0.00399 AC: 608 AN: 152266 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00620

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00635

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00448 AC: 1125 AN: 251132 Hom.: 5 AF XY: 0.00516 AC XY: 701 AN XY: 135756

Gnomad AFR exome AF: 0.000679

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00229

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00788

Gnomad FIN exome AF: 0.00176

Gnomad NFE exome AF: 0.00622

Gnomad OTH exome AF: 0.00538

GnomAD4 exome AF: 0.00576 AC: 8416 AN: 1461822 Hom.: 27 Cov.: 31 AF XY: 0.00587 AC XY: 4270 AN XY: 727200

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00219

Gnomad4 ASJ exome AF: 0.00191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00754

Gnomad4 FIN exome AF: 0.00157

Gnomad4 NFE exome AF: 0.00646

Gnomad4 OTH exome AF: 0.00497

GnomAD4 genome AF: 0.00400 AC: 609 AN: 152384 Hom.: 4 Cov.: 33 AF XY: 0.00357 AC XY: 266 AN XY: 74536

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00641

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00635

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00526 Hom.: 5

Bravo AF: 0.00380

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00605 AC: 52

ExAC AF: 0.00462 AC: 561

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

E2F1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.083
Sift	Benign	0.52	T
Sift4G	Benign	0.97	T
Polyphen		0.93	P
Vest4		0.33
MVP		0.48
MPC		1.1
ClinPred		0.016	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.091
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs145741678; hg19: chr20-32268180; COSMIC: COSV104413340; COSMIC: COSV104413340;